Pre-filled syringe

ABSTRACT

The invention relates to a pre-filled syringe, an auto-injector device comprising such pre-filled syringe, a method of administering a pharmaceutical composition with such auto-injector device, and a manufacturing method for such auto-injector device. The pre-filled syringe comprises a container and a needle. The container is filled with a pharmaceutical composition comprising epinephrine, a buffer, and water. The buffer is configured to buffer in a pH range between 3 and 4. The needle is adhered to the container by means of a urethane acrylate or urethane methacrylate acrylic light cure adhesive, which is configured to provide a pull out resistance of the needle relative to the container which is between 30 N to 100 N, preferably between 50 N to 70 N, more preferably greater than 60 N after 90 days exposure to the pharmaceutical composition at 40° C. and 75% relative humidity (RH). In an example, the pharmaceutical composition is for the treatment of an anaphylactic event.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a divisional of U.S. patent application No.15/405,877, filed Jan. 13, 2017, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to a pre-filled syringe, an auto-injector devicecomprising such syringe, a method of administering a pharmaceuticalcomposition with such auto-injector device, and a manufacturing methodfor such auto-injector device.

BACKGROUND OF THE INVENTION

There are pre-filled syringes available, but in particular syringespre-filled with epinephrine may be further improved. The improvement maybe in particular directed to an increased shelf life of the pre-filledsyringe containing epinephrine.

SUMMARY OF THE INVENTION

Hence, there may be a need to provide a syringe pre-filled withepinephrine, which enables an increased shelf life.

The problem of the present invention is solved by the subject-matter ofthe independent claims, wherein further embodiments are incorporated inthe dependent claims. It should be noted that the aspects of theinvention described in the following apply also to the pre-filledsyringe, the auto-injector device comprising such syringe, the method ofadministering a pharmaceutical composition with such auto-injectordevice, and the manufacturing method for such auto-injector device.

According to the present invention, a pre-filled syringe is presented.The pre-filled syringe may be used for immediate self-administration asemergency treatment of allergic reactions (Type I, including anaphylaxisto stinging insects) delivering 0.15 mg and 0.3 mg of epinephrine atconcentrations of 0.5 mg/mL and 1.0 mg/mL, respectively, as sterilesolution for single use injection by means of an auto-injector.Epinephrine is also known as adrenaline. There may be two types ofauto-injectors available, one for junior (pediatric) and one for adultadministration. Both auto-injectors may be suitable for intramuscular orsubcutaneous administration and for easy use by the lay person as firstaid.

The pre-filled syringe according to the present invention comprises acontainer and a needle. The container is filled with a pharmaceuticalcomposition comprising epinephrine, a buffer, and water. The buffer isconfigured to buffer in a pH range between 3 and 4. The needle isadhered to the container by means of a urethane acrylate or urethanemethacrylate acrylic light cure adhesive, which is configured to providea pull out resistance of the needle relative to the container between 30N to 100 N, preferably between 50 N to 70 N, more preferably greaterthan 60 N after 90 days exposure to the pharmaceutical composition at40° C. and 75% relative humidity (RH). The pull out resistance isdefined the force required to dislodge the needle from the syringe, inparticular dislodge a bonded stainless steel needle from a glasscontainer.

In other words, the pre-filled syringe according to the inventioncomprises epinephrine and a buffer configured to buffer in a pH rangebetween 3 and 4 to minimize degradation reactions and to thereby keepthe composition stable, and a needle adhered to a container by means ofa urethane acrylate or urethane methacrylate acrylic light cure adhesiveconfigured to keep above defined pull out resistance stable. As asynergetic effect, the stable composition avoids more severe attacks ofthe composition on the adhesive and the stable adhesive avoids moresevere attacks of the surrounding oxygen on the composition.Consequently, the shelf life of the pre-filled syringe is greatlyincreased.

The very complex interdependences between the components of thepharmaceutical composition, the pH range, the urethane acrylate orurethane methacrylate acrylic light cure adhesive and the pull outresistance will be explained in much detail in the following:

The Components of the Pharmaceutical Composition and the pH Range

Epinephrine is chemically unstable in aqueous solution and undergoes avariety of degradation reactions such as racemization, oxidation,photodegradation, hydrolysis, and substitution reactions. The rates ofthese multiple degradation reactions depend on the complex interplay ofpH, dissolved oxygen available bisulfites and light. The multipledegradation pathways may occur consecutively and in parallel.

The major degradation routes of the pharmaceutically more potentL-adrenaline are oxidation, racemization and sulfonation by additivessuch as sodium metabisulfite employed as an antioxidant. The products ofthese reactions, such as D-adrenaline, L- or D-adrenaline sulfonate,leucoadrenochrome or adrenochrome possess little or no pharmacologicalactivity compared with the parent L-adrenaline compound. Epinephrineracemization occurs easily in acidic solutions. Rapid oxidation ofepinephrine (in aqueous solutions without antioxidant) results instrongly colored, pharmacologically inactive degradation products.Accordingly, antioxidants may have to be used in the injectableformulations. As the kinetics of racemization decreases and oxidationincrease with increasing the solution pH, there is an optimum pH rangeat which racemization and oxidation are balanced to minimize thesedegradation routes. Incorporation of a buffer configured to buffer in apH range between 3 and 4 is useful to control the pH within a narrowrange.

As a result, the pharmaceutical composition in the pre-filled syringeaccording to the invention comprises epinephrine and the bufferconfigured to buffer in a pH range between 3 and 4 to keep thecomposition stable.

The Urethane Acrylate or Urethane Methacrylate Acrylic Light CureAdhesive

The pharmaceutical composition further influences the mechanicalconnection between the container and the needle. The pre-filled syringecomprises a cylindrical syringe container made of glass or plastic withan injection needle attached thereto. A typical process for themanufacture of pre-filled syringes includes the steps of arranging theneedle in a reception channel of the container and fixing the needle tothe container by use of radiation-curable adhesives, e.g. byUV-irradiation. In an additional step, the syringes might be cleanedwith hot water at about 70° C. Further manufacturing steps may includesiliconization and a couple of sterilization cycles, e.g. 1-3 cycles ofethylene oxide (ETO) sterilization and filling with the drug formulationinjectable product.

At an inner boundary between needle and inner container, the epinephrinedrug formulation might be in direct contact with and/or exposed to theadhesive. In syringes pre-filled with e.g. drug excipients such asbuffers, antioxidants or tonicity agents, leachables/extractables maydissolve from and/or diffuse out of the adhesive leading to orincreasing degradation of the drug product upon storage over longperiods of time and/or at elevated temperatures and/or elevated relativehumidity (e.g. 40° C. and 75% relative humidity (RH)).

Conversely, drug components such as buffers, antioxidants or tonicityagents may dissolve and/or diffuse into the adhesive leading todegradation of the adhesive by components of the pharmaceuticalcomposition. This degradation may lead to a decrease of bonding strengthbetween needle and container, thus the pull out resistance of the needlerelative to the container over the lifetime or shelf life of thepre-filled syringe may significantly decrease. The decrease of the pullout resistance may lead to a detrimental detachment or weakening,breakage of the bond between needle and container while, for example,being pushed with force through clothes and into the skin for anemergency injection. The needle may dislodge early or bend duringinjection resulting in thigh aceration.

To avoid such degradation of the mechanical connection between thecontainer and the needle, the use of a urethane acrylate or urethanemethacrylate acrylic light cure adhesive is presented, which isconfigured to provide a pull out resistance of the needle relative tothe container which is between 30 N to 100 N, preferably between 50 N to70 N, and more preferably greater than 60 N after 90 days exposure tothe pharmaceutical composition at 40° C. and 75% relative humidity (RH).

Examples for such adhesives for stainless needle-glass container bondingare one component heat cured epoxy based structural adhesives. Suchepoxy based structural adhesives, e.g. Loctite 9535, show a superiortensile bonding strength in the range of at least 30-40 N/mm². Otherexamples for such adhesives for stainless needle-glass container bondingare two component epoxy resin structural adhesives such as LoctiteM-21HP, also having a superior tensile bonding strength above 50 N/mm².

Other examples for such adhesives for stainless needle-glass containerbonding are fast-curing, in particular radiation curing adhesives,typically light- or photo-curing adhesives, such as acrylate-basedadhesives, which can be cured by visible light or UV-light. A chemicaltype acrylate of this class is Loctite 3011 having a tensile bondingstrength in the range of 1-5 N/mm².

Urethane acrylate or urethane methacrylate acrylic light cure adhesivescan comprise additives such as fill materials and/or a tougheningagents, tonics, stabilizers, initiators, antipolymering agents. Inurethane acrylate or urethane methacrylate acrylic light cure adhesives,urethane pre-polymers may be end capped with hydroxyl acrylates and/ormethacrylates to build an urethane acrylate or urethane methacrylateoligomer.

Further suitable examples for light cure adhesives for bonding stainlesssteel needles to glass or plastic containers are modified acrylates ormodified methacrylates, comprising an acrylic and/or methacrylic monomerand additives such as fill materials and/or a toughening agents, tonics,stabilizers, initiators, anti-polymerization agents. Such modifiedacrylates may comprise at least one acrylic monomer or component such asN,N-dimethylacrylamine, 2-ethoxayethyl acrylate, 2-hydroxylethylactrylate, 2-phenoxyethyl acrylate, butyl acrylate, acrylic acid,cyclohexyl acrylate, dicyclopentenyl acrylate, dodecyl acrylate, ethylacrylate, hydroxylethyl acrylate, methacrylamide, methacrylic acid,methyl acrylate, neopentyl glycol diacrylate, norbonyl diacrylate,phenyl acrylate, triethylene, trimethoxysilyloxpypropyl acrylate andothers. Such modified methacrylates may comprise at least onemethacrylic monomer or component such as 2-methylcylohexyl methacrylate,benzyl methacrylate, butyl, methacrylate, cylohexyl methacrylate,ethoxylated bisphenol A dimethacrylate, ethylene glycoldimethacrylate,hexyl methacrylate, isopropyl methacryklate, methyl, methacrylate,neopentyl methacrylate, phenyl methacrylate, tetraahydrofufurylmethacrylate, triethylene glycol dimethacrylate and others. Suchadditives being designed to increase tensile strength and/or glasstemperature T_(G) for improving steam sterilization stability and/orbetter acidic resistance.

An example of a modified acrylate light cure adhesive is Loctite AA3081. This UV-light curable modified acrylate shows a tensile bondingstrength above 20-30 N/mm² (lower value break strength, higher valueyield strength) and an excellent bond strength retention after beingsubjected to standard sterilization methods, such as steam vaporautoclave, EtO and Gamma Radiation (25 to 50 kiloGrays cumulative).

An example of a urethane methacrylate acrylic light cure adhesive isLoctite 3345. Loctite 3345 shows a low to medium tensile bondingstrength above 7 N/mm² for steel to glass bonding. According to theproduct description/sheet, products similar in composition to Loctite3345 subjected to standard sterilization methods, such as EtO and GammaRadiation (25 to 50 kiloGrays cumulative), show excellent bond strengthretention. Loctite 3345 should maintain bond strength after 1 cycle ofsteam autoclave.

Modified acrylate or modified methacrylate acrylic light cure adhesives,such as Loctite AA 3081 show a superior tensile bonding strengthcompared to urethane acrylate or urethane methacrylate acrylic lightcure adhesives such as Loctite 3345 (above 20-30 N/mm² compared to above7 N/mm²). In addition, modified acrylate or modified methacrylateacrylic light cure adhesives are less sensitive to heat/humidity.Surprisingly, urethane acrylate or urethane methacrylate acrylic lightcure adhesives show a much better pull out resistance preservation whenexposed to a pharmaceutical composition comprising epinephrine, a bufferand water, when the buffer is configured to buffer in a pH range between3 and 4.

As a result, the pre-filled syringe according to the invention comprisesa stainless steel needle adhered to a glass container by means of aurethane acrylate or urethane methacrylate acrylic light cure adhesive,which is configured to keep above defined pull out resistance stable.

The Pull Out Resistance

The pull out resistance is defined as the force required to dislodge theneedle from the syringe, in particular dislodge the bonded stainlesssteel needle from the glass container. In an example, the pull outresistance is between 30 N and 100 N after 90 days exposure to thepharmaceutical composition at 40° C. and 75% relative humidity (RH). Inan example, the pull out resistance is between 50 N and 70 N after 90days exposure to the pharmaceutical composition at 40° C. and 75%relative humidity (RH). In an example, the pull out resistance isgreater than 60 N after 90 days exposure to the pharmaceuticalcomposition at 40° C. and 75% relative humidity (RH). In an example, thepull out resistance is about 60 N after 90 days exposure to thepharmaceutical composition at 40° C. and 75% relative humidity (RH).

In summary, the pre-filled syringe according to the invention comprisesepinephrine and the buffer configured to buffer in a pH range between 3and 4 to keep the composition stable, and the stainless steel needleadhered to the glass container by means of the urethane acrylate orurethane methacrylate acrylic light cure adhesive configured to keepabove defined pull out resistance stable. As a synergetic effect, thestable composition avoids more severe attacks of the composition on theadhesive and the stable non decomposing adhesive avoids more severeattacks of the surrounding oxygen on the composition. Consequently, theshelf life of the pre-filled syringe is greatly increased.

The Needle

The acid pharmaceutical composition may in addition negatively influencethe material of the stainless steel needle leading again to a reducedlifetime or shelf life of the pre-filled syringe. The negative influencemay be corrosion, in particular pitting or intercrystalline corrosionand/or a decrease in mechanical strength. To avoid such negativeinfluences and to increase the corrosion resistance, the stability ofmechanical strength and/or the shelf life, in an example, the needle ismade from high corrosion resistance steel comprising 15 to 20% Cr, 8 to16% Ni and 1 to 4% Mo. For the same reasons, in another example, theneedle is made from high corrosion resistance steel comprising 15 to 25%Cr, 20 to 30% Ni and 3 to 6% Mo.

Needles in a range from 19 G to 25 G may be used for injection of theepinephrine formulation. Needles from 22 G to 25 G are preferred for thepediatric injection. In a most preferred example, a 22 G standard sizeneedle having an outer diameter between 0.69 to 0.74 mm and an innerdiameter between 0.39 to 0.45 mm is used. To decrease injection time orto decrease injection pain (decrease of pain by decrease of outerdiameter), a thin wall needle or a special thin wall, ultra-thin wallneedle might be used. As the needle is used for intramuscular injection,the needle length should be in the range between 0.8 inch to 1.5 inch,respective 20.3 mmm to 38.1 mm for adult injection and between ⅞ inch to1.25 inch, respective 22.2 mm to 31.75 mm for pediatric injection. In amost preferred example, the needle length is between 20 mm to 25 mm. Inan autoinjector, the needle is partially covered and captured by anautoinjector housing. The exposed needle length, as measured from a skincontact to a face of the autoinjector, is between 13 mm to 17 mm 15mm+/−2 mm for the adult injection autoinjector and 13 mm+/−2 11 mm to 15mm for the pediatric injection autoinjector.

The Container

Two dimensions affect dose accuracy of the pre-filled syringe, namely alength of a ram of the syringe and a position of a stopper in thecontainer. In addition, a process of inserting the stopper into thecontainer determines a headspace volume in the syringe which againaffects the dose accuracy. The term “headspace” refers to the gas spaceabove the product in the container. So to improve a dose accuracy, abovementioned dimensions of syringe and stopper (diameter and length) mustbe within predetermined tolerances as well as a process of filling thesyringe and inserting the stopper must be carefully controlled. Based onall possible tolerances and process parameters, the best dose accuracycan be achieved with a slightly overfilled syringe. Therefore in anexample, the container contains between 0.95 ml and 1.07 ml andpreferably between 1.04 and 1.07 ml of the pharmaceutical composition.

Options Concerning the Pharmaceutical Composition

In an example, the epinephrine content is between 0.9 and 1.1 mg/mL foradult patients or between 0.4 and 0.6 mg/mL for pediatric patients. Thepharmaceutical composition may further comprise sodium chloride fortonicity adjustment, sodium metabisulfite (SMBS) as an antioxidantagent, hydrochloric acid as pH adjuster, sodium tartrate as bufferingagent, and water for injection as diluent. The addition of tartratebuffer and a low concentration of antioxidant enhances the stability ofthe formulation without impacting safety and efficacy.

The addition of a buffer as described in the following may enhance thestability of the formulation without impacting safety and efficacy. Inan example, the buffer is configured to buffer at a pH of about 3.4 to4.0 In an example, the buffer is a carboxylic acid. In an example, thebuffer is a bicarboxylic acid. In an example, the buffer is a tartratesalt. In an example, the buffer is sodium tartrate dihydrate.

In an example, the sodium tartrate dihydrate content is between 1.0 and1.6 mg/mL for adult patients or between 0.5 and 0.8 mg/mL for pediatricpatients. In an example, the sodium tartrate dihydrate content is about1.38 mg/mL for adult patients or about 0.69 mg/mL for pediatricpatients.

Also the addition of an antioxidant and its low concentration mayenhance the stability of the formulation without impacting its safetyand efficacy. In an example, the pharmaceutical composition furthercomprises an antioxidant. In an example, the antioxidant content in thepharmaceutical composition is below 1.6 mg/mL. In an example, theantioxidant is sodium metabisulfite. In an example, the sodiummetabisulfite content is between 1.1 and 1.3 mg/mL. In an example, thesodium metabisulfite content in the pharmaceutical composition is about1.2 mg/mL.

In an example, the pharmaceutical composition further comprises a pHadjuster. In an example, the pH adjuster is hydrochloric acid.

In an example, the pharmaceutical composition further comprises atonicity adjuster. In an example, the tonicity adjuster is a sodiumchloride.

According to the present invention, also an auto-injector device ispresented. The auto-injector device comprises a syringe and a firingmechanism. The syringe comprises a needle and a container. The containeris filled with a pharmaceutical composition comprising epinephrine, abuffer, and water. The buffer is configured to buffer in a pH rangebetween 3 and 4. The needle is adhered to the container by means of aurethane acrylate or urethane methacrylate acrylic light cure adhesive,which is configured to provide a pull out resistance of the needlerelative to the container between 30 N to 100 N, preferably between 50 Nto 70 N, more preferably greater than 60 N after 90 days exposure to thepharmaceutical composition at 40° C. and 75% relative humidity (RH). Thefiring mechanism is configured to expel the pharmaceutical compositionfrom the syringe and to inject it into a subject.

There may be two types of auto-injectors available, one for junior(pediatric) and one for adult administration. Both auto-injectors may besuitable for intramuscular or subcutaneous administration. In anexample, the pressure during injection into the subject is in a range of100 to 4000 psi. In an example, the syringe provides about 1 mL of thepharmaceutical composition and the auto-injector device is configured todeliver 0.3 ml of the pharmaceutical composition during a singleinjection in below 0.5 sec, in particular between 0.1 sec and 0.3seconds.

In an example, it was determined whether both auto-injectors, one forjunior (pediatric) 0.15 mg one for adult administration 0.3 mg strengthsare equivalent with respect to the volume of drug that is delivery afteractuating a device. The statistical analysis results show strongequivalence compared to an allowed equivalence range of 0.251 ml to0.349 ml.

In another example a second analysis has been done for comparing twosublots for 0.15 mg strength from the same 100 L compounded solutionthat were filled using same processing conditions, fill volume andvacuum pressure but filled at different time interval.

The individual delivered volume of the epinephrine formulation afteractuation in any of the above examples is in between 0.250 ml and 0.349ml (nominal 0.300 ml), preferably in between 0.27 ml to 0.32 ml (n>50tested PFS epinephrine formulation autoinjector deliveries).

The arithmetic mean of delivered volume of the epinephrine formulationafter actuation in any of the above examples is in between 0.295 ml (95%Lower Confidence Interval for Mean, n>50 tested PFS epinephrineformulation autoinjector deliveries) to 0.305 ml (95% Upper ConfidenceInterval for Mean, n>50 tested PFS epinephrine formulation autoinjectordeliveries).

The auto-injector device and the firing mechanism are further describedwith respect to the drawings.

According to the present invention, also a method of administering apharmaceutical composition with an auto-injector device is presented. Itcomprises the following steps:

-   a) Providing an auto-injector device comprising a syringe and a    firing mechanism. The syringe comprises a needle and a container.    The container is filled with a pharmaceutical composition comprising    epinephrine, a buffer and water. The buffer is configured to buffer    in a pH range between 3 and 4. The needle is adhered to the    container by means of a urethane acrylate or urethane methacrylate    acrylic light cure adhesive, which is configured to provide a pull    out resistance of the needle relative to the container between 30 N    to 100 N, preferably between 50 N to 70 N, more preferably greater    than 60 N after 90 days exposure to the pharmaceutical composition    at 40° C. and 75% relative humidity (RH).-   b) Activating the firing mechanism to expel the pharmaceutical    composition from the syringe and to inject it into a subject.

The method of administering the pharmaceutical composition with theauto-injector device is further described with respect to the drawings.In an example, the pharmaceutical composition is for the treatment of ananaphylactic event. The active ingredient of the pharmaceuticalcomposition is epinephrine also known as adrenaline. It is the drug ofchoice for the emergency treatment of severe allergic reactions (Type I)due to insect stings or bites, foods, drugs and other allergens. It canalso be used in the treatment of anaphylaxis of unknown cause(idiopathic anaphylaxis) or exercise-induced anaphylaxis.

According to the present invention, also a manufacturing method for anauto-injector device is presented. It comprises the following steps:

-   a) Manufacturing a pharmaceutical composition comprising    epinephrine, a buffer and water. The buffer is configured to buffer    in a pH range between 3 and 4.-   b) Sterilizing the pharmaceutical composition.-   c) Filling the pharmaceutical composition in a container of a    syringe. The syringe further comprises a needle. The needle is    adhered to the container by means of a urethane acrylate or urethane    methacrylate acrylic light cure adhesive, which is configured to    provide a pull out resistance of the needle relative to the    container between 30 N to 100 N, preferably between 50 N to 70 N,    more preferably greater than 60 N after 90 days exposure to the    pharmaceutical composition at 40° C. and 75% relative humidity (RH).-   d) Assembling the syringe into an auto-injector device which    comprises a firing mechanism. The firing mechanism is configured to    expel the pharmaceutical composition from the syringe and to inject    it into a subject.

The solution may be protected from light during compounding and fillingand assembly into devices. The protection from light may be ensured byoperating under filtered (amber coloured) light and other lightprotective mechanisms during the respective processes.

In an example, the manufacturing of the pharmaceutical compositioncomprises the following steps:

-   -   preparing a solution comprising the buffer and an antioxidant,    -   adding a pH adjuster to adjust a pH range of the solution        between 2.5 and 4.3,    -   adding epinephrine, and    -   adding a pH adjuster to adjust a pH range of the solution        comprising epinephrine between 3 and 4.

In an example, the pH adjuster is added to adjust a pH value of thesolution comprising epinephrine to about 3.4 to 4.0.

In an example, the manufacturing of the pharmaceutical compositioncomprises the further steps of:

-   -   degassing water, and    -   adding the degassed water to the solution comprising        epinephrine.

Degassed water for injection may be used to minimize a level ofdissolved oxygen to protect the solution during compounding and fillingfrom dissolved oxygen. In an example, the degassing of water comprisesthe steps of a) subjecting water to vacuum, b) sparging the water withnitrogen gas, and c) again subjecting the water to vacuum. In anexample, the water is subjected to vacuum for about 45 minutes in stepa) and in step c). In an example, the water is sparged with nitrogen gasat a minimum of 4 L/min for about 120 minutes.

In an example, the sterilizing of the pharmaceutical compositioncomprises an aseptic filtration. In an example, the aseptic filtrationis done at room temperature by means of a polyvinylidenfluoride filter.In an example, the filter has a pore size in the range of 0.1 to 0.3 μm.

As epinephrine degradation may be facilitated by the presence of oxygenin a headspace of the syringe container, this risk may be reduced byadjusting a stopper placement to an optimum stopper height and lowerheadspace z using vacuum stoppering. The term “headspace z” refers tothe gas space above the product in a container. In an example, thefilling of the pharmaceutical composition in the syringe (with needleguard) is done through an opening.

Term Definitions

The term “epinephrine” refers to4-[(1R)-1-Hydroxy-2-(methylamino)ethyl]-1,2-benzenediol, which isproduced in the adrenal medulla and which is an endogenous catecholaminewhich acts directly on both alpha and beta adrenergic receptors. Whenused in pharmaceutical compositions, epinephrine can act as anon-selective alpha and beta adrenergic agonist and can work rapidly toimprove breathing, stimulate the heart, raise dropping blood pressure,reverse hives, and reduce swelling of the face, lips, and throat. Usesfor epinephrine include emergency treatment of allergic reactions (Type1), including anaphylaxis, induction and maintenance of mydriasis duringintraocular surgery, treatment of bronchospasm, sensitivity reactions,cardiac arrhythmias, GI and renal hemorrhage, superficial bleeding,premature labor, hypoglycemia, and cardiogenic, hemorrhagic, andtraumatic shock. Epinephrine can also be used to increase blood flow inadvanced cardiac life support (ACLS) during Cardiac-PulmonaryResuscitation (CPR), as an adjunct to local anesthesia, and forradiographic uses. The concentration of epinephrine within thepharmaceutical composition for administration to adult patients is 0.7to 1.5 mg/ml, preferably 0.8 to 1.3 mg/ml, more preferably 0.9 to 1.1mg/ml and most preferably it is 1.0 mg/ml. The concentration ofepinephrine within the pharmaceutical composition for administration topediatric patients is 0.2 to 0.8 mg/ml, preferably 0.3 to 0.7 mg/ml,more preferably 0.4 to 0.6 mg/ml and most preferably it is 0.5 mg/ml.

The term “buffer” refers to a component present in a composition orsolution which may provide a resistance to a significant change in pHcaused by a strong acid or base. A buffer may comprise a single agent ormore than one agent, such as a weak acid and its conjugate base. Abuffer may provide a resistance to a significant pH change byinteracting with a strong acid or strong base in a composition orsolution, thereby at least partially preventing the pH of thecomposition or solution from changing significantly. Generally, a bufferhas one or more buffer ranges wherein the buffer has the ability toprovide resistance to significant pH change. When a composition orsolution comprising the buffer has a pH inside the buffer's bufferrange, the pH of the composition or solution will not changesignificantly with the addition of equimolar amounts of a strong acid orstrong base.

The term “antioxidant” refers to a component in a composition that mayprevent and/or inhibit the formation of unacceptable amounts of oxidizedspecies in the composition after a certain period of shelf life. In someembodiments, the antioxidant may react with oxygen that might otherwisecompromise the composition by producing impurities in the composition.Oxygen may originate from the composition's environment or thecomposition itself. For example, oxygen may originate from residualoxygen present in the headspace of vials containing the composition.Suitable antioxidants include, but are not limited to, sodiummetabisulfite, sodium sulfite, ascorbic acid, cysteine, cystin andglutathione. Preferably, sodium metabisulfite is used as antioxidant.

The term “tonicity” refers to the effective osmotic pressure equivalentof a solution or composition. Further, tonicity is the ‘effectiveosmolality’ and is equal to the sum of the concentrations of the soluteswhich have the capacity to exert an osmotic force across the membrane. A“tonicity adjuster” adjusts the tonicity of a pharmaceutical compositionso that it is isotonic with body fluids, in particular blood. Suitabletonicity adjusters include salts such as sodium chloride and potassiumchloride and sugars such as mannitol, dextrose, sucrose and trehalose aswell as glycerol. Preferably sodium chloride is used as a tonicityadjuster. The concentration of the tonicity adjuster and preferably ofsodium chloride is 20 to 200 mM, preferably 40 to 150 mM, morepreferably 80 to 120 mM and most preferably 100 mM.

A pH adjuster is an acid or a base which is just to establish a specificpH of the pharmaceutical composition. Suitable acids includehydrochloric acid, acetic acid, citric acid and sodium phosphate.

The term “shelf life” refers to the length of time that a product may bestored without becoming unfit for medical use. Examples of compositionswhich are unfit for medical use include, but are not limited to,compositions with high impurity levels that are not toxilogicalqualified and/or the presence of physical changes described herein, suchas colour change and/or the presence of insoluble particles.

It shall be understood that the pre-filled syringe, the auto-injectordevice comprising such syringe, the method of administering apharmaceutical composition with such auto-injector device, and themanufacturing method for such auto-injector device according to theindependent claims have similar and/or identical preferred embodiments,in particular, as defined in the dependent claims. It shall beunderstood further that a preferred embodiment of the invention can alsobe any combination of the dependent claims with the respectiveindependent claim.

These and other aspects of the present invention will become apparentfrom and be elucidated with reference to the embodiments describedhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the invention will be described in thefollowing with reference to the accompanying drawings:

FIG. 1 shows schematically and exemplarily an exploded view of anembodiment of an auto-injector device according to the invention.

FIG. 2 shows schematically and exemplarily an exploded view of an A-halfof the auto-injector device.

FIG. 3 shows schematically and exemplarily an exploded view of a B-halfof the auto-injector device.

FIG. 4 shows schematically and exemplarily delivery stages for theauto-injector device.

FIG. 5 shows a schematic overview of steps of a method of administeringa pharmaceutical composition with an auto-injector device.

FIG. 6 shows a schematic overview of steps of a manufacturing method foran auto-injector device.

DETAILED DESCRIPTION OF EMBODIMENTS

The invention relates to a pre-filled syringe 10, an auto-injectordevice 20 comprising such pre-filled syringe 10, a method ofadministering a pharmaceutical composition with such auto-injectordevice 20, and a manufacturing method for such auto-injector device 20.

The active ingredient of the present drug product is epinephrine USPalso known as adrenaline. It is the drug of choice for the emergencytreatment of severe allergic reactions (Type I) due to insect stings orbites, foods, drugs and other allergens. It can also be used in thetreatment of anaphylaxis of unknown cause (idiopathic anaphylaxis) orexercise-induced anaphylaxis.

Each auto-injector for adults delivers a single dose of 0.3 mgepinephrine injection, USP, 1:1000 (0.3 mL) in a sterile solution. Eachauto-injector for juniors delivers a single dose of 0.15 mg epinephrineinjection, USP, 1:2000 (0.3 mL) in a sterile solution. Theauto-injectors each contain 1 mL epinephrine solution. Approximately 0.7mL remains in the auto-injector after activation and cannot be used.

FIG. 1 shows schematically and exemplarily an exploded view of anembodiment of an auto-injector device 20 according to the invention forimmediate self-administration emergency treatment for allergic reactions(anaphylaxis). The auto-injector device 20 is a single-use, disposable,spring-powered, non-sterilized device for sterile drug delivery. Theepinephrine drug product is available in two strengths (junior andadult) with the same auto-injector. Both junior and adult are designedto administer 0.3 mL of epinephrine drug product from the 1.0 mLcontents of a pre-filled syringe 10 during a single injection.

There is no drug fluid pathway within the auto-injector device 20;therefore the auto-injector device 20 does not come in contact with thecontents of the pre-filled syringe 10. The auto-injector device 20consists of two sub-assemblies (A-half and B-half) into which apre-filled syringe 10 is assembled to form a final delivery system.

The auto-injector device 20 comprises a pre-filled syringe 10 and afiring mechanism 21. The pre-filled syringe 10 comprises a needle 12 anda container 11. The container 11 is filled with a pharmaceuticalcomposition comprising epinephrine, a buffer, and water. The buffer isconfigured to buffer in a pH range between 3.4 to 4.0. The needle 12 isadhered to the container 11 by means of a urethane methacrylate acryliclight cure adhesive, wherein the urethane methacrylate acrylic lightcure adhesive is configured to provide a pull out resistance of theneedle 12 relative to the container 11 which is greater than 60 N after90 days exposure to the pharmaceutical composition at 40° C. and 75% RH.The firing mechanism 21 is configured to expel the pharmaceuticalcomposition from the syringe and to inject it into a subject.

FIG. 2 shows schematically and exemplarily an exploded view of theA-half of the auto-injector device 20. The A-half of the auto-injectordevice 20 comprises a rear housing 21, which contains the components inthe A-half sub-assembly and is designed to permanently attach to aB-half front housing 35 via a snap clip. The A-half comprises at leastone safety clip 22 onto the back of the rear housing 21, which isremoved just prior to the injection. The safety clip 22 thereby preventsinadvertent triggering of the auto-injector device 20 and inadvertentretraction of a needle guard 34 once a safety cap 36 has been removed.The A-half further comprises a latch 23, which houses a main spring 24and retains a ram 25 so that the main spring 24 is compressed in apreloaded state. The A-half further comprises a trigger 26, whichprevents the latch 23 from releasing the ram 25 until the needle guard34 sufficiently retracts to dislodge the trigger 26; thereby freeing theram 25 to move under the force of a main spring 24. The retention of theram 25 is achieved via two prongs that grasp the end of the ram 25, whenthe trigger 26 is dislodged the prongs release the ram 25. The A-halffurther comprises the main spring 24, which stores energy in itspreloaded state which is used to displace the ram 25 delivering theformulation when the trigger 26 is dislodged by the latch 23. The A-halffurther comprises the ram 25, which drives a syringe stopper therequired distance when the auto-injector device 20 is activated todeliver the formulation to a patient.

FIG. 3 shows schematically and exemplarily an exploded view of theB-half of the auto-injector device 20. The B-half comprises a syringebushing 31, which removes a clearance between the syringe and a sleeve32 and compensates for the variability seen in the dimensionalcharacteristics of the glass pre-filled syringe 10. The B-half furthercomprises the sleeve 32, which locates the syringe within the body ofthe auto-injector device 20 and mechanically clips to the latch 23 inthe A-half assembly. The sleeve 32 has a safety feature, such that ifthe flanges of the syringe fail, then the safety feature within thesleeve 32 (that is, the sleeve 32 syringe catcher) will retain thesyringe to allow correct device operation. The B-half further comprisesthe return spring 33, which keeps the needle guard 34 in the extendedposition until an injection is initiated. After the injection has beencompleted, the return spring 33 then automatically re-extends the needleguard 34, which “locks out” the device; thereby preventing the usedsyringe needle 12 from being re-exposed. The B-half further comprisesthe needle guard 34, which protects the pre-filled syringe needle priorto and after the injection. During the injection, the needle guard 34retracts to expose the needle 12. During activation of the auto-injectordevice 20, the legs of the needle guard 34 dislodge the trigger 26 andforce it away from the latch 23. This allows the force of the mainspring 24 to push the ram 25 free of the two prongs on the end of thelatch 23; allowing the main spring 24 to drive the ram 25 forward todeliver the contents of the syringe. The B-half further comprises afront housing 35, which contains all of the parts in the B-halfsub-assembly and is designed to snap fit with the A-half rear housing 21after the syringe has been inserted. The front housing 35 has an arrowprinted on it with the text “Needle End” to indicate which end theneedle 12 comes out of and therefore which end should be applied to thethigh. The B-half further comprises the safety cap 36, which preventsinadvertent retraction of the needle guard 34. When the safety cap 36 isremoved, it also removes a needle shield from the syringe (not shown) inpreparation for the injection. The safety cap 36 also has an arrowprinted on it with the text “Twist” to indicate which direction thesafety cap 36 needs to be twisted for removal.

FIG. 4 shows schematically and exemplarily delivery stages for theauto-injector device 20. The auto-injector device 20 is not ready to usewhen received, as the safety clip 22 and safety cap 36 are in place, asshown in FIG. 4 ; top left. The safety clip 22 and the safety cap 36 arefirst removed before the auto-injector device 20 is ready to use.Removal of the safety cap 36 removes the needle shield. The needle guard34 covers the pre-filled syringe needle 12 and houses the needle shield.The return spring 33 is situated inside the needle guard 34 whichextends the needle guard 34 until activation. In the top of theauto-injector device 20, the trigger 26 constrains the latch 23 so thatthe ram 25 is retained. This prevents the main spring 24 from displacingthe ram 25. In this figure, the main spring 24 is in its fullycompressed state.

At the start of injection (FIG. 4 ; top right), the needle guard 34 isfully retracted and the needle 12 exposed. In this position the legs ofthe needle guard 34 have dislodged the trigger 26, such that the trigger26 no longer constrains the two prongs of the latch 23. The two prongssit in an indentation groove at the end of the ram 25. With the trigger26 in place around the prongs, the prongs cannot flex outward andtherefore the prongs retain the ram 25. Once the trigger 26 is movedupward, it no longer constrains the latch prongs. Thus, the ram 25 isfree to be pushed downward by the force of the main spring 24.

At the end of injection (FIG. 4 ; bottom left), the ram 25 has extendedpast the lock out features on the latch 23 and come to rest against theflange of the pre-filled syringe 10. Ram 25 displacement is limited byits leading collar contacting the outer face of the syringe flange.After injection and when the needle 12 is removed from the injectionsite, the needle guard 34 extends such that the needle 12 is shrouded(FIG. 4 ; bottom right). Lock out clip features present on the needleguard legs interact with lockout clip features on the latch 23,preventing displacement of the needle guard 34 and providing a lockoutfunction for sharps protection.

Epinephrine is chemically unstable in solution and it can undergo aseries of complex reactions in the product including oxidation,hydrolytic and substitution reactions. Epinephrine also undergoes aseries of chemical, enzymatic, and metabolic pathways upon injectioninto the human body. The rates of these reactions depend on the complexinterplay of light, pH, dissolved oxygen and available bisulfites. Indetail:

An aqueous solution of epinephrine is sensitive to light and undergoesdegradation even when subjected to natural light. Photo-stability ofepinephrine is dependent on the epinephrine concentration and thepresence of other formulation additives. Light is also known to catalyzethe oxidation reaction of epinephrine. The photo-degradation kinetics ofepinephrine appears to be faster in the presence of bisulfite than inits absence. Therefore, epinephrine must be protected from light orunder filtered light during compounding.

Epinephrine is oxidized rapidly by molecular oxygen and other oxidizingagents to produce colour forming oxidized species. This discoloration ispharmaceutically unacceptable and appropriate antioxidants are necessaryto stabilize epinephrine formulations. one particularly suitableantioxidant is sodium metabisulfite.

Oxidation appears to be catalyzed by light and hence protection fromlight is required. The rate of oxidation also increases with increasingpH of the formulation. However, formulating at low pH is not a viableoption because the rate of another degradation pathway, i.e.,racemization, increases with decreasing pH. In conclusion, stabilizationof epinephrine in the formulation and avoiding formation of colouredimpurities requires optimization of pH, lack of exposure to light andoxygen during manufacturing and in the product, and incorporation of anantioxidant such as sodium metabisulfite (SMBS). SMBS is also known toreact readily with epinephrine to form sulfonated impurities. Therefore,the SMBS level is optimized to ensure satisfactory product attributes.

Sodium metabisulfite, by preferential oxidation, protects epinephrinefrom oxidation by molecular oxygen. The preferential oxidation yieldssulfate species that result in a pH decrease as bisulfate is a strongeracid than bisulfite. This reaction has an indirect implication onepinephrine stability as the pH of the formulations decreases on storageas a result of sulfite oxidation.

The mechanism of sulfite (or bisulfite) oxidation depends on bisulfiteconcentration. Therefore, an optimum concentration of bisulfite isselected for use as antioxidant such that it predominantly reacts onlywith dissolved oxygen as an antioxidant, but minimally contribute tosulfonation reactions.

While bisulfite protects epinephrine from oxidation, it reacts withepinephrine itself to form a pharmacologically inactive sulfonate. Therate of sulfonation reaction increases with an increase in pH. Asbisulfite is used as an antioxidant in formulations of epinephrine, careis taken to adjust the concentration of drug, antioxidant, and pH to anoptimum value to ensure maximum stability.

Considering all these competing reactions that depend on pH, it isimperative to incorporate a buffer (in the pH range of 2-5, and morespecifically 3-4) into the epinephrine solution to enhance its chemicalstability. The buffer is preferably a carboxylic acid and morepreferably a dicarboxylic acid. Dicarboxylic acids are characterized bytwo functional carboxyl groups and include linear saturated dicarboxylicacids such as oxalic acid, malonic acid, succinic acid, glutaric acid,adipic acid, pimelic acid and suberic acid, branched-chain dicarboxylicacids, unsaturated dicarboxylic acids such as maleic acid and fumaricacid and substituted dicarboxylic acids such as malic acid, asparticacid, glutamic acid and tartaric acid. Among the various dicarboxylicacids that can act as buffer in the pH range between 2 and 5, tartaricacid is preferred to buffer the epinephrine formulation, becausetartaric acid is a bicarboxylic acid with pK_(a) values of 3.03 and 4.37A carboxylic acid exerts a strong buffering capacity within the pH rangeof pK_(a)±0.5 units and less so at pK_(a)±1.0. Based on this, tartaricacid exerts strong buffering capacity in the desired pH range between2.5 (3.03−0.50) and 4.9 (4.37+0.50). Further, epinephrine has beenreported to form salt with tartaric acid as epinephrine bitartrate.

The concentration of the tartrate buffer in the pharmaceuticalcomposition for administration to pediatric patients is between 0.3 and1 mg/ml, preferably between 0.4 mg/ml and 0.9 mg/ml, more preferablybetween 0.5 mg/ml and 0.8 mg/ml and most preferably it is 0.69 mg/mL.The concentration of the tartrate buffer in the pharmaceuticalcomposition for administration to adult patients is between 0.8 and 2mg/ml, preferably between 1.0 mg/ml and 1.6 mg/ml, more preferablybetween 1.2 mg/ml and 1.5 mg/ml and most preferably it is 1.38 mg/mL.

As discussed earlier, addition of an antioxidant such as SMBS as isrequired for epinephrine stability. However, excess SMBS itself willreact with epinephrine through sulfonation reaction. In addition, only0.25 mM of SMBS is required to consume all (0.25 mM) the dissolvedoxygen in water at atmospheric temperature and pressure. Hence, foroptimum stability of epinephrine, it is useful to reduce the SMBSconcentration that is added. As a result of this reduction in SMBSconcentration, less epinephrine sulfonic acid would be formed. Hence,the concentration of sodium metabisulfite in the pharmaceuticalcomposition is 0.5 to 1.8 mg/ml, preferably 0.7 to 1.5 mg/ml, morepreferably 1.0 to 1.4 mg/ml and most preferably it is 1.2 mg/ml.

In one embodiment, the pharmaceutical composition comprises epinephrine,sodium chloride, sodium metabisulfite, sodium tartrate dihydrate andwater for injection and the pH is adjusted with hydrochloric acid. Inone embodiment, the pharmaceutical composition for administration toadults comprises 1 mg/ml epinephrine, 100 mM sodium chloride, 1.2 mg/mlsodium metabisulfite, 1.38 mg/ml sodium tartrate dihydrate and water forinjection and the pH is adjusted with hydrochloric acid. In oneembodiment, the pharmaceutical composition for administration topediatric patients comprises 0.5 mg/ml epinephrine, 100 mM sodiumchloride, 1.2 mg/ml sodium metabisulfite, 0.69 mg/ml sodium tartratedihydrate and water for injection and the pH is adjusted withhydrochloric acid.

As a summary, the pre-filled syringe according to the inventioncomprises epinephrine and a buffer configured to buffer in a pH rangebetween 3 and 4 to minimize degradation reactions and to thereby keepthe composition stable, and a needle adhered to a container by means ofa urethane methacrylate acrylic light cure adhesive configured to keepabove defined pull out resistance stable. As a synergetic effect, thestable composition avoids more severe attacks of the composition on theadhesive and the stable adhesive avoids more severe attacks of thesurrounding oxygen on the composition. Consequently, the shelf life ofthe pre-filled syringe is greatly increased.

FIG. 5 shows a schematic overview of steps of a method of administeringa pharmaceutical composition with an auto-injector device 20. The methodcomprises the following steps:

In a first step S1, providing an auto-injector device 20 comprising asyringe and a firing mechanism 21. The syringe comprises a needle 12 anda container 11. The container 11 is filled with a pharmaceuticalcomposition comprising epinephrine, a buffer, and water. The buffer isconfigured to buffer in a pH range between 3 and 4. The needle 12 isadhered to the container 11 by means of a urethane methacrylate acryliclight cure adhesive, which is configured to provide a pull outresistance of the needle 12 relative to the container 11 which isgreater than 60 N after 90 days exposure to the pharmaceuticalcomposition at 40° C. and 75% RH.

In a second step S2, activating the firing mechanism 21 to expel thepharmaceutical composition from the syringe and to inject it into asubject.

FIG. 6 shows a schematic overview of steps of a manufacturing method foran auto-injector device 20. The method comprises the following steps:

In a first step T1, manufacturing a pharmaceutical compositioncomprising epinephrine, a buffer, and water. The buffer is configured tobuffer in a pH range between 3 and 4. The manufacturing method for thepharmaceutical composition may be described as follows. About 100 L ofwater for injection (WFI) is dispensed into a 100 L stainless steeltank. To reduce the dissolved oxygen content, degassed WFI is used.Degassing was done by vacuum for 45 min and then sparged with nitrogengas at a minimum of 4 L/min for about 2 h and then finally under vacuumfor 45 min. About 80% of the batch weight of degassed WFI is dispensedfrom the stainless steel tank into a compounding vessel. The excipients(sodium chloride, sodium metabisulfite, sodium tartrate, and HCl) aredispensed into the compounding vessel and mixed to yield a clearsolution. Then, the diluted solution (DS) is dispensed into thecompounding vessel and mixed for DS dissolution. The pH is adjusted tothe target pH value using HCl. The remaining amount of WFI is added toreach the final target weight.

In a second step T2, sterilizing the pharmaceutical composition. Thesterilization relies on the input of sufficient energy to be lethal toany potential microbial contamination. The used methods may compriseheat and irradiation. The pharmaceutical composition or epinephrine bulksolution can be sterilized by continuous filtration through two(redundant) sterile 0.22 μm PVDF filters during filling. The container11 and closures are “ready to use” components i.e., sterilized by gammairradiation.

In a third step T3, filling the pharmaceutical composition into a barrelor container 11 of a syringe. The syringe further comprises a needle 12made of stainless steel 316 L. The needle 12 is adhered to a rubberstopper put into an opening of the container 11 by means of a urethanemethacrylate acrylic light cure adhesive as e.g. Loctite 3345. Theadhesive is configured to provide a pull out resistance of the needle 12relative to the container 11 which is greater than 60 N after 90 daysexposure to the pharmaceutical composition at 40° C. and 75% RH. Thepull out resistance may also be defined to be between 80 N and 95 Nafter 90 days exposure to the pharmaceutical composition at 40° C. and75% relative humidity (RH).

In a fourth step T4, assembling the syringe into an auto-injector device20 which comprises a firing mechanism 21. The firing mechanism 21 isconfigured to expel the pharmaceutical composition from the syringe andto inject it into a subject.

In other words, the manufacturing of the pharmaceutical compositionstarts with weighing degassed water for injection into a compoundingtank and dissolving excipients. Then, to the excipient solution,dispensed amount of API is added followed by predetermined quantity ofHCl. After completion of dissolution, pH of the solution is adjusted tothe target pH of between 3 and 4 with further amount of HCl. Thecompounded bulk solution is continuously sterile filtered and filledinto the container 11 or the barrel of the pre-filled syringe 10, whichis then sealed with a rubber stopper under vacuum.

As epinephrine degradation may be facilitated by the presence of oxygenin a headspace of the syringe barrel or container 11, this risk may bereduced by adjusting a stopper placement to an optimum stopper heightand lower headspace. The term “headspace” refers to the gas space abovethe product in a container. The headspace gas may be manipulated inorder to reduce the amount of oxygen present therein. In detail:

During a filling process, a needle 12 goes into the syringe and fillsthe syringe with 1.04 mL of formulation. After filling, the needle 12 isremoved and appropriate vacuum setting is reached and the desired dwelltime has passed, the insertion rod pushes the stopper into the top ofthe syringe barrel to a specified position. The stopper height relies onthe fill volume and the applied vacuum pressure. The stopper placementis checked via manual and automated inspection. The liquid level in thesyringe relative to the syringe top flange depends on the fill volumeand internal diameter (ID) of the syringe. The inner diameter of thesyringe cartridge is preferably between 6.25 mm to 6.45 mm, nominal 6.35mm. The tolerance in the precise volume fill is preferably below 0.03ml. The opening is closed after the filling by an inserted rubberstopper. Vacuum is supplied to pull the stopper thru the syringe barrelfrom flange to top of the fill volume. The stopper is inserted into thesyringe at the desired vacuum pressure setpoint within the followingrange for example, 28-44 mbar.

The container may be made of glass, containing a chlorobutyl elastomericrubber stopper as container closure system for product, and the needlemay be made of stainless steel 316 L.

The dose accuracy or delivered dose is mainly influenced by theheadspace z and the stopper height (i.e., plunger position). The stopperheight, distance between stopper rear face and the end face of thesyringe's flange, relies on the syringes tolerance in length, thesyringe ID, the tolerance in stopper length and on the applied vacuumpressure (ie lower vacuum pressure setpoint corresponds to a strongervacuum) and dwell time at the stopper insertion process The syringelength tolerance shall be between 0.2 to 1 mm, preferably equal or below0.5 mm. The tolerance in stopper length shall be between 0.2 to 0.8 mm,preferably equal or below 0.4 mm and the tolerance in the stopper widthis 0.0-0.2 mm.

After insertion of the stopper air pressure is returned to atmosphericpressure and the stopper moves forward to contact the fluid with leavinga headspace z above the liquid level. In an example contributors to avariation in dose delivered could be plunger position (gap betweenram/plunger end face and stopper rear face), variation in ram/plungerlength, plunger mechanical dynamic and an effective displacement of thestopper due to an air bubble at the headspace z. Of these contributorseffective displacement of the stopper due to an air bubble is thelargest contributor.

To compensate headspace volume associated with potential bubbles anddeliver at least 0.25 ml, preferably more than 0.28 ml of epinephrineformulation and a nominal volume of 1.04 ml is filled into the syringeat a vacuum pressure setpoint of 28-44 mbar (ie, a higher vacuumpressure set point corresponds to a weaker vacuum and results in smallerstopper height and a greater deliverable volume). Thus a nominal dose of0.3 ml, preferably between 0.28 ml to 0.34 ml of the pharmaceuticalepinephrine composition/formulation is injected.

A first batch of 616 auto-injectors containing epinephrine at aconcentration of 1 mg/mL was tested with respect to the volume ofepinephrine that was delivered after actuating a device. The meandelivered volume was 0.299 ml with a Standard Deviation (Std Dev) ofless than 0.015 ml (95% Upper and Lower Confidence Interval for Mean).

A second batch of 1197 auto-injectors containing epinephrine at aconcentration of 0.5 mg/mL was tested with respect to the volume ofepinephrine that was delivered after actuating a device. The meandelivered volume was 0.302 ml with a Standard Deviation (Std Dev) ofless than 0.010 ml (95% Upper and Lower Confidence Interval for Mean).

It has to be noted that embodiments of the invention are described withreference to different subject matters. In particular, some embodimentsare described with reference to method type claims whereas otherembodiments are described with reference to the device type claims.However, a person skilled in the art will gather from the above and thefollowing description that, unless otherwise notified, in addition toany combination of features belonging to one type of subject matter alsoany combination between features relating to different subject mattersis considered to be disclosed with this application. However, allfeatures can be combined providing synergetic effects that are more thanthe simple summation of the features.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Theinvention is not limited to the disclosed embodiments. Other variationsto the disclosed embodiments can be understood and effected by thoseskilled in the art in practicing a claimed invention, from a study ofthe drawings, the disclosure, and the dependent claims.

In the claims, the word “comprising” does not exclude other elements orsteps, and the indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfil the functions ofseveral items re-cited in the claims. The mere fact that certainmeasures are re-cited in mutually different dependent claims does notindicate that a combination of these measures cannot be used toadvantage. Any reference signs in the claims should not be construed aslimiting the scope.

Example 1 represents an example formulation composition of thepharmaceutical composition comprised in the pre-filled syringe forepinephrine injection according to the invention.

Ingredients Function Adult Junior Epinephrine Active 1.0 mg/mL 0.5 mg/mLSodium Tonicity 6 mg/mL 6 mg/mL Chloride adjustment Sodium Antioxidant1.2 mg/mL 1.2 mg/mL Metabisulfite Sodium Buffer 1.38 mg/mL 0.69 mg/mLTartrate dihydrate Hydrochloric pH adjuster pH 2.2-5.0 pH 2.2-5.0 AcidWater for Vehicle Q.S Q.S Injection

Further Embodiments

-   1. A pre-filled syringe (10) comprising a container (11) and a    needle (12),    -   wherein the container (11) is filled with a pharmaceutical        composition comprising epinephrine, a buffer, and water;    -   wherein the buffer is configured to buffer in a pH range between        3 and 4,    -   wherein the needle (12) is adhered to the container (11) by        means of a urethane acrylate or urethane methacrylate acrylic        light cure adhesive, and    -   wherein the urethane acrylate or urethane methacrylate acrylic        light cure adhesive is configured to provide a pull out        resistance of the needle (12) relative to the container (11)        which is greater than 60 N after 90 days exposure to the        pharmaceutical composition at 40° C. and 75% RH.-   2. Pre-filled syringe (10) according to embodiment 1, wherein the    needle (12) is made from high corrosion resistance steel comprising    15 to 20% Cr, 8 to 16% Ni and 1 to 4% Mo.-   3. Pre-filled syringe (10) according to embodiment 1, wherein the    needle (12) is made from high corrosion resistance steel comprising    15 to 25% Cr, 20 to 30% Ni and 3 to 6% Mo.-   4. Pre-filled syringe (10) according to claim 1, wherein the    container (11) contains between 0.95 ml and 1.07 ml, and preferably    between 1.04 and 1.07 ml of the pharmaceutical composition.-   5. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the needle (12) has an inner diameter (ID)    between 0.39 to 0.53 mm.-   6. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the buffer is a bicarboxylic acid.-   7. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the buffer is a tartrate salt.-   8. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the buffer is sodium tartrate dihydrate.-   9. Pre-filled syringe (10) according to the preceding embodiment,    wherein the sodium tartrate dihydrate content is between 1.0 and 1.6    mg/mL for adult patients or between 0.5 and 0.8 mg/mL for pediatric    patients.-   10. Pre-filled syringe (10) according to embodiment (, wherein the    sodium tartrate dihydrate content is about 1.38 mg/mL for adult    patients or about 0.69 mg/mL for pediatric patients.-   11. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the pharmaceutical composition further    comprises an antioxidant,    -   wherein the antioxidant is sodium metabisulfite, and    -   wherein the sodium metabisulfite content in the pharmaceutical        composition is about 1.2 mg/mL.-   12. Pre-filled syringe (10) according to one of the preceding    embodiments, wherein the pharmaceutical composition further    comprises a pH adjuster and a tonicity adjuster,    -   wherein the pH adjuster is a hydrochloric acid,    -   wherein the tonicity adjuster is a sodium chloride, and    -   wherein the epinephrine content is between 0.9 and 1.1 mg/mL for        adult patients or between 0.4 and 0.6 mg/mL for pediatric        patients.-   13. An auto-injector device (20), comprising:    -   a pre-filled syringe (10) according to one of the preceding        embodiments, and    -   a firing mechanism (21),    -   wherein the firing mechanism (21) is configured to expel a        pharmaceutical composition from the pre-filled syringe (10) and        to inject it into a subject.-   14. Auto-injector device (20) according to the preceding embodiment,    wherein the pressure during injection into the subject is in a range    of 100 to 4000 psi.-   15. Auto-injector device (20) according to one of the preceding    embodiments, wherein the pre-filled syringe (10) provides about 1 mL    of the pharmaceutical composition and the auto-injector device (20)    is configured to deliver about 0.3 ml of the pharmaceutical    composition during a single injection in below 0.5 sec.-   16. A manufacturing method for an auto-injector device (20),    comprising the following steps:    -   manufacturing a pharmaceutical composition comprising        epinephrine, a buffer, and water, wherein the buffer is        configured to buffer in a pH range between 3 and 4,    -   sterilizing the pharmaceutical composition,    -   filling the pharmaceutical composition in a container (11) of a        pre-filled syringe (10) according to one of the preceding        embodiments 1 to 12, and    -   assembling the pre-filled syringe (10) into an auto-injector        device (20) comprising a firing mechanism (21), wherein the        firing mechanism (21) is configured to expel the pharmaceutical        composition from the pre-filled syringe (10) and to inject it        into a subject.-   17. Manufacturing method according to the preceding embodiment,    wherein the manufacturing of the pharmaceutical composition    comprises the following steps:    -   preparing a solution comprising the buffer and an antioxidant,    -   adding a pH adjuster to adjust a pH range of the solution        between 2.5 and 4.3,    -   adding epinephrine, and    -   adding a pH adjuster to adjust a pH range of the solution        comprising epinephrine between 3 and 4.-   18. Manufacturing method according to one of the preceding    embodiments, wherein the pH adjuster is added to adjust a pH value    of the solution comprising epinephrine to about 3.4.-   19. Manufacturing method according to one of the preceding    embodiments, wherein the manufacturing of the pharmaceutical    composition comprises the further steps of    -   degassing water, and    -   adding the degassed water to the solution comprising        epinephrine,    -   wherein the degassing of water comprise the steps of:        -   a) subjecting water to vacuum,        -   b) sparging the water with nitrogen gas, and        -   c) again subjecting the water to vacuum.-   20. Manufacturing method according to the preceding embodiment,    wherein the water is subjected to vacuum for about 45 minutes in    step a) and in step c).-   21. Manufacturing method according to one of the preceding    embodiments, wherein the water is sparged with nitrogen gas at a    minimum of 4 L/min for about 120 minutes.-   22. Manufacturing method according to one of the preceding    embodiments, wherein the sterilizing of the pharmaceutical    composition comprises an aseptic filtration.-   23. Manufacturing method according to the preceding embodiment,    wherein aseptic filtration is done at room temperature by means of a    polyvinylidenfluoride filter.-   24. Manufacturing method according to the preceding embodiment,    wherein the filter has a pore size in the range of 0.1 to 0.3 μm.-   25. Manufacturing method according to one of the preceding    embodiments, wherein the filling of the pharmaceutical composition    in the pre-filled syringe (10) is done through an opening, wherein    the opening is closed after the filling by a stopper, and a flange    surrounding the opening is subjected to vacuum forcing air below the    stopper to be removed from the syringe.-   26. A method of administering a pharmaceutical composition with an    auto-injector device (20), comprising the following steps:    -   providing an auto-injector device (20) according to one of the        preceding embodiments, and    -   activating the firing mechanism (21) of the auto-injector device        (20) to expel a pharmaceutical composition from a pre-filled        syringe (10) of the auto-injector device (20) and to inject it        into a subject.-   27. Method according to the preceding embodiment, wherein the    pharmaceutical composition is for the treatment of an anaphylactic    event.

The invention claimed is:
 1. A manufacturing method for anauto-injector, the manufacturing method comprising: manufacturing apharmaceutical composition, the pharmaceutical composition comprisingepinephrine, a buffer, and water, wherein the pharmaceutical compositionhas a pH ranging between 3 and 4; sterilizing the pharmaceuticalcomposition; adhering a stainless steel needle to a glass container withan adhesive, wherein the adhesive comprises at least one of a urethaneacrylate adhesive or a urethane methacrylate adhesive; filling the glasscontainer with at least 1 mL of the pharmaceutical composition to form apre-filled container; and assembling the pre-filled container into theauto-injector, wherein the auto-injector is for single use injection andcomprises a firing mechanism, wherein the firing mechanism is configuredto expel only a single injection of about 0.3 mL of the at least 1 mL ofthe pharmaceutical composition from the pre-filled container, and thefiring mechanism is configured to expel the single injection in lessthan 0.5 seconds.
 2. The manufacturing method of claim 1, wherein themanufacturing of the pharmaceutical composition comprises: preparing asolution comprising the buffer and an antioxidant; adding a pH adjusterto adjust a pH of the solution to a range between 2.5 and 4.3; addingthe epinephrine; and adding, after adding the epinephrine, the pHadjuster or another pH adjuster to adjust a pH of the solutioncomprising the epinephrine to a range between 3 and
 4. 3. Themanufacturing method of claim 2, wherein the pH adjuster or the other pHadjuster is added to adjust the pH of the solution comprising theepinephrine to about 3.4.
 4. The manufacturing method of claim 1,wherein the sterilizing of the pharmaceutical composition comprisesperforming an aseptic filtration.
 5. The manufacturing method of claim4, wherein performing the aseptic filtration occurs at room temperaturewith a polyvinylidenfluoride filter.
 6. The manufacturing method ofclaim 5, wherein the polyvinylidenfluoride filter has a pore sizeranging between 0.1 [tm and 0.3 [tm.
 7. The manufacturing method ofclaim 1, wherein the glass container is filled with the pharmaceuticalcomposition through an opening, and wherein the opening is closed afterthe filling by a stopper using a vacuum stoppering technique.
 8. Themanufacturing method of claim 1, wherein the stainless steel needlecomprises 15 to 20% Cr, 8 to 16% Ni, and 3 to 4% Mo.
 9. Themanufacturing method of claim 1, wherein the stainless steel needlecomprises 15 to 20% Cr, 20 to 30% Ni, and 3 to 6% Mo.
 10. Themanufacturing method of claim 1, wherein the buffer comprises at leastone of bicarboxylic acid, tartrate salt, or sodium tartrate dihydrate.11. The manufacturing method of claim 1, wherein the pharmaceuticalcomposition further comprises an antioxidant.
 12. The manufacturingmethod of claim 11, wherein the antioxidant comprises sodiummetabisulfite.
 13. The manufacturing method of claim 1, wherein thefiring mechanism is configured to expel the pharmaceutical compositionfrom the pre-filled container at a pressure ranging between 100 psi and4000 psi.
 14. The manufacturing method of claim 1, wherein, after theadhesive is exposed to the pharmaceutical composition for 90 days at 40°C. and 75% relative humidity, the adhesive is configured to resist apull out force of between 30 N and 100 N applied to at least one of thestainless steel needle or the glass container.
 15. The manufacturingmethod of claim 1, wherein the firing mechanism is configured such thatat least about 0.7 mL of the at least 1 mL of the pharmaceuticalcomposition remains in the auto-injector after the single injection. 16.The manufacturing method of claim 15, wherein the auto-injector isconfigured to prevent the at least about 0.7 mL of the at least 1 mL ofthe pharmaceutical composition from being expelled from the pre-filledcontainer.
 17. The manufacturing method of claim 16, wherein the firingmechanism comprises a ram configured to expel the pharmaceuticalcomposition from the pre-filled container, and wherein, after the singleinjection, the ram is configured to rest against the pre-filledcontainer to prevent another injection of the pharmaceutical compositionfrom the pre-filled container.
 18. A manufacturing method for anauto-injector, the manufacturing method comprising: degassing watercomprising: subjecting the water to a vacuum to form vacuumed water,sparging the vacuumed water with nitrogen gas to form sparged water, andsubjecting the sparged water to a vacuum to form degassed water;manufacturing a pharmaceutical composition, the pharmaceuticalcomposition comprising epinephrine, a buffer, and the degassed water,wherein the pharmaceutical composition has a pH ranging between 3 and 4;sterilizing the pharmaceutical composition; adhering a stainless steelneedle to a glass container with an adhesive, wherein the adhesivecomprises at least one of a urethane acrylate adhesive or a urethanemethacrylate adhesive; filling the glass container with at least 1 mL ofthe pharmaceutical composition to form a pre-filled container; andassembling the pre-filled container into the auto-injector, wherein theauto-injector comprises comprising a firing mechanism, wherein thefiring mechanism is configured to expel the pharmaceutical compositionfrom the pre-filled container.
 19. The manufacturing method of claim 18,wherein the water is subjected to the vacuum for about 45 minutes. 20.The manufacturing method of claim 18, wherein the vacuumed water issparged with the nitrogen gas at a minimum of 4 L/min for about 120minutes.
 21. The manufacturing method of claim 18, wherein, after theadhesive is exposed to the pharmaceutical composition for 90 days at 40°C. and 75% relative humidity, the adhesive is configured to resist apull out force of between 30 N and 100 N applied to at least one of thestainless steel needle or the glass container.
 22. The manufacturingmethod of claim 18, wherein the firing mechanism is configured to expelabout 0.3 mL of the pharmaceutical composition from the pre-filledcontainer in less than 0.5 seconds-during a single injection.
 23. Themanufacturing method of claim 18, wherein the sterilizing of thepharmaceutical composition comprises performing an aseptic filtration.24. The manufacturing method of claim 18, wherein the glass container isfilled with the pharmaceutical composition through an opening, andwherein the opening is closed after the filling by a stopper using avacuum stoppering technique.
 25. The manufacturing method of claim 18,wherein the firing mechanism is configured to expel the pharmaceuticalcomposition from the pre-filled container at a pressure ranging between100 psi and 4000 psi.
 26. The manufacturing method of claim 18, whereinthe buffer comprises at least one of bicarboxylic acid, tartrate salt,or sodium tartrate dihydrate.
 27. The manufacturing method of claim 18,wherein the pharmaceutical composition further comprises an antioxidant.